Polycyclic amine derivatives useful as cerebrovascular agents

ABSTRACT

A method for the treatment of cerebrovascular disorders by administering a fluorenamine, dibenzofuranamine, or dibenzothiophenamine derivative.

BACKGROUND OF THE INVENTION

The present invention covers a series of fluorenamine, dibenzofuranamineand dibenzothiophenamines, derivatives useful in the treatment ofcerebrovascular disorders.

U.S. Pat. Nos. 3,159,677, 3,206,480 and 3,111,527 are concerned withfluorenamines, dibenzofuranamines, dibenzothiophenamines and processesfor preparing them. The compounds have useful central nervous systemdepressant activity.

Excessive excitation by neurotransmitters can cause the degeneration anddeath of neurons. It is believed that this excitotoxic action ismediated by the excitatory amino acids, glutamate and aspartate, actingat the N-methyl-D-aspartate (NMDA) receptor. This action is responsiblefor neuronal loss in cerebrovascular disorders such as: cerebralischemia or cerebral infarction resulting from a range of conditionssuch as thromboembolic or hemorrhagic stroke, cerebral vasospasm,hypoglyceMia, cardiac arrest, status epilepticus, perinatal asphyxia,anoxia such as from drowning, pulmonary surgery and cerebral trauma.Thus the compounds of the instant invention which are active asnoncompetitive antagonist of NMDA receptor mediated ion channelactivation are useful in the treatment of the above disorders. Inaddition, by this NMDA antagonist action, the compounds of the instantinvention are also useful for treating schizophrenia, epilepsy,spasticity, neurodegenerative disorders such as Alzheimer's disease, orHuntington's disease, Olivo-pontocerebellar atrophy, spinal cord injury,and poisoning by exogenous NMDA poisons (e.g. some forms of lathyrism).Further uses are as analgesics J. Pharmacol. Exp. Ther., 243, 9, (1987)and anesthetics, particularly for use in surgical procedures where afinite risk of cerebrovascular damage exists.

There are no specific therapies for these neurodegenerative disorders,but competitive and non-competitive NMDA antagonists acting specificallyto antagonize excitatory neurotransmission at NMDA receptors offer anovel therapeutic approach to these disorders; B. Meldrum in"Neurotoxins and Their Pharmacological Implications" edited by P.Jenner, Raven Press, New York, 1987. Recent literature reports haveconfirmed the protective action of examples of this class of agents inpharmacological models of neurodegenerative disorders (J. W. Mcdonald,F. S. Silverstein and M. V. Johnston, Eur. J. Pharmacol., 140, 359,(1987); R. Gill, A. C. Foster and G. N. Woodruff, J. Neurosci., 7, 3343,(1987); S. M. Rothman, J. H. Thurston, R. E. Hauhart, G. D. Clark and J.S. Soloman, Neurosci., 21, 673, (1987); M. P. Goldberg, P-C. Pham and D.W. Choi, Neurosci. Lett., 80, 11, (1987).

The present invention provides a method of prevention and/or treatmentof the aforementioned pathological conditions by the administration ofspecific, orally active non-competitive NMDA receptor antagonists.

SUMMARY OF THE INVENTION

The present invention provides a method of treatment for cerebrovasculardisorders which comprises specific non-competitive NMDA antagonists offormula ##STR1## wherein R₁ -R₄, Z and A are defined herein below.

Preferred compounds of the present invention are those

wherein:

Z is methylene or sulfur;

R₁ is hydrogen, methyl, ethyl, propyl or (CH₂)₃ OMe;

R₂ is hydrogen or methyl;

R₃, R₄ are each hydrogen;

A is --CH₂ CH₂ --, --CH═CH-- or when Z is methylene, A is additionally--CH(Me)CH₂ --.

Preferred compounds of the instant invention are:

1,4,9,9a-tetrahydro-4aH-fluoren-4a-amine,

1,4,9,9a-tetrahydro-N-methyl-4aH-fluoren-4a-amine,

1,4,9,9a-tetrahydro-N,N-dimethyl-4aH-fluoren-4a-amine,

N-ethyl-1,4,9,9a-tetrahydro-4aH-fluoren-4a-amine,

1,4,9,9a-tetrahydro-N-propyl-4aH-fluoren-4a-amine,

N-butyl-1,4,9,9a-tetrahydro-4aH-fluoren-4a-amine,

1,4,9,9a-tetrahydro-N-pentyl-4aH-fluoren-4a-amine,

1,4,9,9a-tetrahydro-3-methyl-4aH-fluoren-4a-amine,

1,4,9,9a-tetrahydro-3-methyl-N-methyl-4aH-fluoren-4a-amine,

1,4,9,9a-tetrahydro-3-methyl-N-ethyl-4aH-fluoren-4a-amine,

N-ethyl-1,2,3,4,9,9a-hexahydro-4aH-fluoren-4a-amine,

1,2,3,4,9,9a-hexahydro-N,N-dimethyl-4aH-fluoren-4a-amine,

N-ethyl-1,2,3,4,9,9a-hexahydro-4aH-fluoren-4a-amine,

1,2,3,4,9,9a-hexahydro-N-propyl-4aH-fluoren-4a-amine,

1,2,3,4,9,9a-hexahydro-2,3-dimethyl-N-methyl-4aH-fluoren-4a-amine,

6,7,8,9-tetrahydro-9a(5aH)-dibenzofuranamine,

6,7,8,9-tetrahydro-N-methyl-9a(5aH)-dibenzofuranamine,

N-ethyl-6,7,8,9-tetrahydro-N-methyl-9a(5aH)-dibenzofuranamine,

6,7,8,9-tetrahydro-N-propyl-9a(5aH)-dibenzofuranamine,

6,7,8,9-tetrahydro-N-(methoxypropyl)-9a(5aH)-dibenzofuranamine,

N-ethyl-6,7,8,9-tetrahydro-N-methyl-9a(5aH)-dibenzothiophenamine,

6,9-dihydro-N-methyl-9a(5aH)-dibenzothiophenamine,

6,9-dihydro-N,N-dimethyl-9a(5aH)-dibenzothiophenamine,

2,5,6,7,8,9-hexahydro-N-methyl-4bH-fluoreno[2,3-d]-1,3-dioxole-4b-amine,and

N-ethyl-2,5,6,7,8,9-hexahydro-4bH-fluoreno[2,3-d]-1,3-dioxole-4b-amine.

Especially preferred compounds of the instant invention are:

N-ethyl-6,7,8,9-tetrahydro-9a(5aH)-dibenzofuranamine,

6,7,8,9-tetrahydro-N-methyl-9a(5aH)-dibenzothiophenamine,

1,2,3,4,9,9a-hexahydro-4aH-fluoren-4a-amine,

1,2,3,4,9,9a-hexahydro-N-methyl-4aH-fluoren-4a-amine,

1,2,3,4,9,9a-hexahydro-N-(3-methoxypropyl)-4aH-fluoren-4a-amine, and

1,2,3,4,9,9a-hexahydro-3-methyl-N-methyl-(4aH)-fluoren-4a-amine.

Also included is a method of administering the compounds.

A method of using the compounds as analgesics is also included.

DETAILED DESCRIPTION

The present invention provides for a method of treatingneurodegenerative disorders by administering a pharmaceuticallyeffective dose of a compound of formula ##STR2## or a pharmaceuticallyacceptable acid addition salt thereof wherein:

Z is methylene, oxygen, or sulfur;

R₁ is hydrogen, lower alkyl, or lower alkoxyalkyl;

R₂ is hydrogen or lower alkyl;

R₃ and R₄ are each independently hydrogen or when taken together aremethylenedioxy;

A is --CH₂ CH₂ --, --CH═CH-- or when Z is methylene A is --CMe═CMe--,--CHMeCHMe--, --CHMeCH₂ --, --CMe═CH--, --CH₂ CH₂ --, or --CH═CH--.

Compounds were prepared using the general routes outlined in the patentsreferenced above and in J. Org. Chem., 28, 1112, (1963).

The term alkyl, except where otherwise stated, in alkyl per se or inalkoxyalkyl is a straight or branched chain of from one to six carbonatoms.

The term alkoxyalkyl is selected from among alkoxy radicals containingnot more than six carbon atoms and includes but is not limited tomethoxy, ethoxy, propyloxy, and the like.

The preferred compounds are those of formula I

wherein:

Z is methylene or sulfur;

R₁ is hydrogen, methyl, ethyl, propyl, or (CH₂)₃ OMe;

R₂ is hydrogen or methyl; and

A is --CH₂ CH₂ --, --CH═CH-- or when Z is methylene, A is --CMe═CMe--,--CHMeCHMe--, --CHMeCH₂ --, --CMe═CH--, --CH₂ CH₂ --, or --CH═CH--.

Table I below provides an easy reference for examples of the invention##STR3##

                  TABLE I                                                         ______________________________________                                        Ex-                                                                           ample R.sub.1    R.sub.2                                                                              R.sub.3                                                                             R.sub.4                                                                            Z    A                                     ______________________________________                                         1    H          H      H     H    CH.sub.2                                                                           CH.sub.2 CH.sub.2                      2    Me         H      H     H    CH.sub.2                                                                           CH.sub.2 CH.sub.2                      3    Me         Me     H     H    CH.sub.2                                                                           CH.sub.2 CH.sub.2                      4    Et         H      H     H    CH.sub.2                                                                           CH.sub.2 CH.sub.2                      5    nPr        H      H     H    CH.sub.2                                                                           CH.sub.2 CH.sub.2                      7    (CH.sub.2).sub.4 Me                                                                      H      H     H    CH.sub.2                                                                           CH.sub.2 CH.sub.2                      8    (CH.sub.2).sub.3 OMe                                                                     H      H     H    CH.sub.2                                                                           CH.sub.2 CH.sub.2                      9    Me         H      --OCH.sub.2 O--                                                                        CH.sub.2                                                                           CH.sub.2 CH.sub.2                       10    Et         H      --OCH.sub.2 O--                                                                        CH.sub.2                                                                           CH.sub.2 CH.sub.2                       11    (CH.sub.2).sub.3 OMe                                                                     H      --OCH.sub.2 O--                                                                        CH.sub.2                                                                           CH.sub.2 CH.sub.2                       12    Me         H      H     H    CH.sub.2                                                                           CH(Me)CH.sub.2                        13    Me         H      H     H    CH.sub.2                                                                           CHMeCHMe                              14    nPr        H      H     H    CH.sub.2                                                                           CHMeCHMe                              15    H          H      H     H    CH.sub.2                                                                           CH═CH                             16    Me         H      H     H    CH.sub.2                                                                           CH═CH                             17    Me         Me     H     H    CH.sub.2                                                                           CH═CH                             18    Et         H      H     H    CH.sub.2                                                                           CH═CH                             19    nPr        H      H     H    CH.sub.2                                                                           CH═CH                             20    H          H      H     H    CH.sub.2                                                                           CMe═CMe                           21    Me         H      H     H    CH.sub.2                                                                           CMe═CMe                           22    Me         Me     H     H    CH.sub.2                                                                           CMe═CMe                           23    Et         H      H     H    CH.sub.2                                                                           CMe═CMe                           24    nPr        H      H     H    CH.sub.2                                                                           CMe═CMe                           25    Me         H      H     H    O    CH.sub.2 CH.sub.2                     26    Me         Et     H     H    O    CH.sub.2 CH.sub.2                     27    Et         H      H     H    O    CH.sub.2 CH.sub.2                     28    nPr        H      H     H    O    CH.sub.2 CH.sub.2                     29    (CH.sub.2).sub.3 OMe                                                                     H      H     H    O    CH.sub.2 CH.sub.2                     30    Me         H      H     H    S    CH.sub.2 CH.sub.2                     31    Me         Et     H     H    S    CH.sub.2 CH.sub.2                     32    Me         H      H     H    S    CH═CH                             33    Me         Me     H     H    S    CH═CH                             34    Me         Et     H     H    S    CH═CH                             ______________________________________                                    

Compounds of the instant invention include solvates, hydrates, and saltsof the compounds of formula I above.

A compound of formula I above is useful both in the free base form andin the form of acid addition salts and both forms are within the scopeof the invention. The term pharmaceutically acceptable acid additionsalt is intended to mean relatively nontoxic acid addition salts fromeither inorganic or organic acids such as, for example, hydrochloric,hydrobromic, sulfuric, phosphoric, citric, oxalic, malonic, acetic,maleic, salicylic, ethanesulfonic, malic, gluconic, fumaric, succinic,ascorbic, methanesulfonic, benzenesulfonic, p-toluenesulfonic, and thelike as would occur to one skilled in the art.

The acid addition salts of the basic compounds are prepared either bydissolving the free base in aqueous or aqueous-alcohol solution or othersuitable solvents containing the appropriate acid and isolating the saltby evaporating the solution, or by reacting the free base and acid in anorganic solvent, in which case the salt separates directly or can beobtained by concentration of the solution.

In applications of this invention, the compounds can be used either asfree bases or in the form of acid addition salts. The acid additionsalts are preferred where greater water solubility is desired.

The compounds used in the invention may contain asymmetric carbon atoms.This invention includes the use of individual enantiomers,diastereomers, or mixtures thereof, which may be prepared or isolated bymethods known in the art.

The compounds of the instant invention may be administered in anyconvenient or effective method for introducing foreign substances intothe blood stream of mammals such as by oral, rectal, or parenteralroutes. The effective dosage level is for example 0.01 to 50 mg/kg,preferably about 0.05 to 10 mk/kg and especially about 0.05 to 0.5mg/kg/day and may be administered on a regimen of 1 to 4 times per day.

The pharmaceutical formulations comprising the NMDA receptor antagonistsof this invention may be conveniently tablets, pills, capsules, powders,or granules for oral administration; sterile parenteral solutions orsuspensions for parenteral administration; or as suppositories forrectal administration.

The compounds useful in the novel method of treatment of this inventionbind with a high affinity and displace [³H]-1-[(2-thienyl)cyclohexyl]piperidine([³ H]TCP) from membranes of therat brain cortex in a reversible and saturable manner. In addition,these useful compounds also inhibit hypoxia and glutamate stimulatedinflux of calcium into cultured rat cortical neurons.

PHARMACOLOGY

The ability of the compounds of the instant invention to interact withphencyclidene (PCP) receptors is shown in Table II. Tritiated TCPbinding, designated RBS1, was carried out essentially as described in J.Pharmacol. Exp. Ther., 238, 739-748 (1986).

The ability of the compounds of the instant invention to inhibit theglutamate and hypoxia stimulated influx of calcium into cultured ratcortical neurons is shown in Table III and Table IV respectively. Themethodology for determining the ability of the compounds of the instantinvention to inhibit the glutamate stimulated calcium influx (GCI) intocultured rat cortical neurons is to be found in: A. W. Probert and F. W.Marcoux, Soc. Neurosci. Abstr., 13, Part II, 754, (1987). Using asimilar culture system, the ability of the compounds of the instantinvention to inhibit the hypoxia stimulated influx of calcium (HCI) wasdetermined by incubating cultured cells in an atmosphere of nitrogen(95%) and CO₂ (5%) at 37° C. for a period of 4 hours. Calcium influx wasdetermined by subtraction of the stimulated influx in the presence oftetrodotoxin (3 μM) and magnesium (10 mM) from that found in the absence(control) and in the presence of the test substance.

                  TABLE II                                                        ______________________________________                                        Inhibition of [.sup.3 H]TCP Receptor Binding                                  Ex-                                          RBS1                             ample R.sub.1    R.sub.2                                                                             R.sub.3                                                                           R.sub.4                                                                           Z    A        IC.sub.50                        ______________________________________                                         1    H          H     H   H   CH.sub.2                                                                           CH.sub.2 CH.sub.2                                                                      27 nM                             2    Me         H     H   H   CH.sub.2                                                                           CH.sub.2 CH.sub.2                                                                      15 nM                             8    (CH.sub.2).sub.3 OMe                                                                     H     H   H   CH.sub.2                                                                           CH.sub.2 CH.sub.2                                                                      102 nM                           12    Me         H     H   H   CH.sub.2                                                                           CH(Me)CH.sub.2                                                                         95 nM                            27    Et         H     H   H   O    CH.sub.2 CH.sub.2                                                                      141 nM                           30    Me         H     H   H   S    CH.sub.2 CH.sub.2                                                                      10 nM                            --    PCP        --    (reference                                                                             --       40 nM                                                       standard)                                              --    TCP        --    (reference                                                                             --       9 nM                                                        standard)                                              --    ketamine   --    (reference                                                                             --       860 nM                                                      standard)                                              --    MK-801     --    (reference                                                                             --       3 nM                                                        standard)                                              ______________________________________                                    

As can be seen in the above table (Table II), examples 1, 2, 8, 12, 27and 30 are potent inhibitors of [³ H]TCP receptor binding and as such,are potent noncompetitive NMDA receptor antagonists. In particular,examples 1, 2 and 30 exhibit a potency comparable to both TCP andMK-801, the most potent noncompetitive NMDA antagonist reported to date.

                  TABLE III                                                       ______________________________________                                        Inhibition of Glutamate Stimulated [.sup.45 Ca] Influx (GCI)                  Ex-                                          GCI                              ample R.sub.1    R.sub.2                                                                             R.sub.3                                                                           R.sub.4                                                                           Z    A        IC.sub.50                        ______________________________________                                         1    H          H     H   H   CH.sub.2                                                                           CH.sub.2 CH.sub.2                          2    Me         H     H   H   CH.sub.2                                                                           CH.sub.2 CH.sub.2                                                                      304 nM                            8    (CH.sub.2).sub.3 OMe                                                                     H     H   H   CH.sub.2                                                                           CH.sub.2 CH.sub.2                                                                      1900 nM                          12    Me         H     H   H   CH.sub.2                                                                           CH(Me)CH.sub.2                                                                         1900 nM                          27    Et         H     H   H   O    CH.sub.2 CH.sub.2                                                                      1800 nM                          30    Me         H     H   H   S    CH.sub.2 CH.sub.2                                                                      260 nM                           --    PCP        --    (reference                                                                             --       160 nM                                                      standard)                                              --    ketamine   --    (reference                                                                             --       5500 nM                                                     standard)                                              --    MK-801     --    (reference                                                                             --       51 nM                                                       standard)                                              ______________________________________                                    

As can be seen in the above table (Table III), examples 2, 8, 12, 27 and30 inhibit the glutamate stimulated influx of calcium into culturedcortical neurons. In particular examples 2 and 30 exhibited similaractivity to MK-801. Since glutamate stimulated influx of calcium intoneurons has been postulated to be the critical factor in neuronal celldeath, the compounds of the instant invention would exhibit aneuroprotective action.

                  TABLE IV                                                        ______________________________________                                        Inhibition of Hypoxia Induced [.sup.45 Ca] Influx (HCI)                       Ex-                                          HCI                              ample R.sub.1    R.sub.2                                                                             R.sub.3                                                                           R.sub.4                                                                           Z    A        IC.sub.50                        ______________________________________                                         1    H          H     H   H   CH.sub.2                                                                           CH.sub.2 CH.sub.2                                                                      167 nM                            2    Me         H     H   H   CH.sub.2                                                                           CH.sub.2 CH.sub.2                                                                      5 nM                              8    (CH.sub.2).sub.3 OMe                                                                     H     H   H   CH.sub.2                                                                           CH.sub.2 CH.sub.2                                                                      43 nM                            12    Me         H     H   H   CH.sub.2                                                                           CH(Me)CH.sub.2                                                                         95 nM                            27    Et         H     H   H   O    CH.sub.2 CH.sub.2                                                                      124 nM                           30    Me         H     H   H   S    CH.sub.2 CH.sub.2                                                                      200 nM                           --    PCP        --    (reference                                                                             --       45 nM                                                       standard)                                              --    ketamine   --    (reference                                                                             --       1900 nM                                                     standard)                                              --    MK-801     --    (reference                                                                             --       34 nM                                                       standard)                                              ______________________________________                                    

As can be seen in the above table (Table IV), examples 1, 2, 8, 12, 27and 30 are potent inhibitors of hypoxia induced calcium influx intocultured neurons. It is believed that the cerebral damage resulting fromischemic, hypoxic, hypoglycemic and other related cerebrovasculardisorders results in the release of excess glutamic and aspartic acidsfrom endogenous neuronal stores. The result of such release is thepathologic influx of calcium into neurons and subsequent cell death. Thedata provided in this table further strongly supports the use of thecompounds of the instant invention as effective therapeutic agents forthe treatment of stroke and related cerebrovascular disorders.

We claim:
 1. A method for treating cerebrovascular disorders whichcomprises administering to a patient a therapeutically effective amountof a compound of the formula ##STR4## or a pharmaceutically acceptableacid addition salt thereof wherein: Z is methylene, oxygen, or sulfur;R₁is hydrogen, lower alkyl, or lower alkoxyalkyl; R₂ is hydrogen or loweralkyl; R₃ and R₄ are each independently hydrogen or when taken togetherare methylenedioxy; A is --CH₂ CH₂ --, --CH═CH-- or when Z is methyleneA is --CMe═CMe--, --CHMeCHMe--, --CHMeCH₂ --, --CMe═CH--, --CH₂ CH₂ --,or --CH═CH--.
 2. A method for treating cerebrovascular disordersaccording to claim 1 wherein in a compound of formula I:Z is methyleneor sulfur, R₁ is hydrogen, methyl, ethyl, propyl, or (CH₂)₃ OMe, R₂ ishydrogen or methyl, and A is --CH₂ CH₂ --, --CH═CH-- or when Z ismethylene A is also --CH(Me)CH₂ --.
 3. A method for treatingcerebrovascular disorders according to claim 1 wherein the compound isselected from the group consistingof:1,4,9,9a-tetrahydro-4aH-fluoren-4a-amine,1,4,9,9a-tetrahydro-N-methyl-4aH-fluoren-4a-amine,1,4,9,9a-tetrahydro-N,N-dimethyl-4aH-fluoren-4a-amine,N-ethyl-1,4,9,9a-tetrahydro-4aH-fluoren-4a-amine,1,4,9,9a-tetrahydro-N-propyl-4aH-fluoren-4a-amine,N-butyl-1,4,9,9a-tetrahydro-4aH-fluoren-4a-amine,1,4,9,9a-tetrahydro-N-pentyl-4aH-fluoren-4a-amine,1,4,9,9a-tetrahydro-3-methyl-4aH-fluoren-4a-amine,1,4,9,9a-tetrahydro-3-methyl-N-methyl-4aH-fluoren-4a-amine,1,4,9,9a-tetrahydro-3-methyl-N-ethyl-4aH-fluoren-4a-amine,N-ethyl-1,2,3,4,9,9a-hexahydro-4aH-fluoren-4a-amine,1,2,3,4,9,9a-hexahydro-N,N-dimethyl-4aH-fluoren-4a-amine,N-ethyl-1,2,3,4,9,9a-hexahydro-4aH-fluoren-4a-amine,1,2,3,4,9,9a-hexahydro-N-propyl-4aH-fluoren-4a-amine, 1.2,3,4,9,9a-hexahydro-2,3-dimethyl-N-methyl-4aH-fluoren-4a-amine,6,7,8,9-tetrahydro-9a(5aH)-dibenzofuranamine,6,7,8,9-tetrahydro-N-methyl-9a(5aH)-dibenzofurananamine,N-ethyl-6,7,8,9-tetrahydro-N-methyl-9a(5aH)-dibenzofuranamine,6,7,8,9-tetrahydro-N-propyl-9a(5aH)-dibenzofuranamine,6,7,8,9-tetrahydro-N-(methoxypropyl)-9a(5aH)-dibenzofuranamine,N-ethyl-6,7,8,9-tetrahydro-N-methyl-9a(5aH)-dibenzothiophenamine,6,9-dihydro-N-methyl-9a-(5aH)-dibenzothiophenamine,6,9-dihydro-N,N-dimethyl-9a-(5aH)-dibenzothiophenamine,2,5,6,7,8,9-hexahydro-N-methyl-4bH-fluoreno[2,3-d]-1,3-dioxole-4b-amine,andN-ethyl-2,5,6,7,8,9-hexahydro-4bH-fluoreno[2,3-d]-1,3-dioxole-4b-amine.4. A method according to claim 1 wherein the compoundis:N-ethyl-6,7,8,9-tetrahydro-9a(5aH)-dibenzofuranamine.
 5. A methodaccording to claim 1 wherein the compoundis:6,7,8,9-tetrahydro-N-methyl-9a(5aH)-dibenzothiophenamine.
 6. A methodaccording to claim 1 wherein the compoundis:1,2,3,4,9,9a-hexahydro-4aH-fluoren-4a-amine.
 7. A method according toclaim 1 wherein the compoundis:1,2,3,4,9,9a-hexahydro-N-(3-methoxypropyl)-4aH-fluoren-4a-amine.
 8. Amethod according to claim 1 wherein the compoundis:1,2,3,4,9,9a-hexahydro-N-methyl-4aH-fluoren-4a-amine.
 9. A methodaccording to claim 1 wherein the compoundis:1,2,3,4,9,9a-hexahydro-3-methyl-N-methyl-4aH-fluoren-4a-amine.
 10. Amethod according to claim 1 wherein 0.01 to 50 mg/kg by weight of acompound or pharmaceuticaly acceptable salt thereof is administered to apatient.
 11. A method of using as an analgesic a compound of formula##STR5## or a pharmaceutically acceptable acid addition salt thereofwherein: Z is methylene, oxygen, or sulfur;R₁ is hydrogen, lower alkyl,or lower alkoxyalkyl; R₂ is hydrogen or lower alkyl; R₃ and R₄ are eachindependently hydrogen or when taken together are methylenedioxy; A is--CH₂ CH₂ --, --CH═CH-- or when Z is methylene A is --CMe═CMe--,--CHMeCHMe--, --CHMeCH₂ --, --CMe═CH--, --CH₂ CH₂ --, or --CH═CH--.